Multiple sclerosis (MS) is the major inflammatory disease of the central nervous system. The principal autoimmune (AI) model of MS is experimental allergic encephalomyelitis (EAE). Genetics, environment and gene-by-environment interactions contribute to disease susceptibility and progression in both MS and EAE. We recently demonstrated that Yeae, a locus on the Y chromosome, influences susceptibility to EAE in both male and female mice. Because only male progeny inherit the Y chromosome, it might be assumed that the effects of Yeae would be restricted to males;however, we proved that Yeae also influences EAE in adult females. It is a major gap in our knowledge how the organizational masculinization of EAE in female mice by Yeae is achieved. In this application we propose to test the hypothesis that gestational microchimerism of female progeny with male cells is the mechanism whereby Yeae leads to the organizational masculinization of EAE in female mice. Specifically, in Aim 1 we will study EAE in all-female, all-male and mixed sex manipulated litters generated by in vitro fertilization and transfer of sex-selected embryos to surrogate females. This will directly ascertain whether or not the Yeae effect in females is due to exposure to their brothers in utero. Additionally, the transcriptomes and immune responses (Aim 2) will be characterized. Lastly, in Aim 3 we will test the hypothesis that Yeae may be Sry and that interaction between Yeae and autosomal loci control the organizational masculinization of EAE in females. PUBLIC HEALTH RELEVANCE: The result of these studies are directly relevant to the recent finding of increased microchimerism in MZ twins concordant for MS and have the potential to significantly enhance our understanding of the role that the gestational environment plays in `fetal programming'of susceptibility and resistance to adult onset AI disease such as MS.